Augmentation of Innate Anti-Microbial Immunity by TLR4 Agonists

描述（由申请人提供）：大面积烧伤导致保护性皮肤屏障的丧失和抗菌防御机制的失调，导致烧伤创面定植和细菌传播到血液、肺和其他组织的理想条件。虽然常规使用局部和全身抗生素，但败血症是烧伤患者在最初的侮辱中存活的长期住院和死亡的最常见原因。随着抗生素耐药菌的日益流行，脓毒症的发生频率和严重程度也随之加剧。因此，需要新的治疗方法来提高严重烧伤患者对感染的抵抗力。我们的研究表明，toll样受体4 （TLR4）激动剂单磷酰脂质A （MPLA）治疗可有效提高小鼠对铜绿假单胞菌烧伤创面败血症的先天宿主抵抗力。MPLA毒性低，目前在临床中广泛用作疫苗佐剂。然而，MPLA增强宿主对全系统细菌感染反应的机制尚不清楚，需要进一步的工作将MPLA在高风险患者中的应用转化为临床环境。本项目的目标是确定tlr4靶向免疫调节剂（如MPLA）在高危人群中提高先天宿主抗感染能力的细胞和分子机制。临床前研究将确定MPLA在烧伤创面感染和烧伤后肺炎的大型动物模型中的安全性和有效性。特异性目的1：确定MPLA增强先天抗菌功能的细胞机制。本研究旨在验证MPLA治疗通过诱导g - csf介导的骨髓中性粒细胞池扩张和中性粒细胞趋化性增强来改善烧伤后感染反应的假设。特异性目的2：定义MPLA增强抗感染能力的细胞内信号改变。这一目标将验证MPLA治疗将导致感染诱导信号通路改变的假设，从而导致PI3K和Trif/IRF-3/IFN¿通路的保护性优势。目的3：确定MPLA在绵羊烧伤创面感染和烧伤后肺炎模型中的安全性和有效性。这一目的将验证MPLA在烧伤羊中耐受性良好的假设，并将改善它们对伤口感染和肺炎的反应。这些研究的结果将促进tlr4靶向免疫调节剂的临床应用，并将通过推进我们对基于tlr的免疫调节剂提高宿主抗感染能力的细胞和分子机制的理解，填补重要的知识空白。

DESCRIPTION (provided by applicant): Large surface area burns cause loss of the protective skin barrier and dysregulation of antimicrobial defense mechanisms resulting in ideal conditions for colonization of burn wounds and dissemination of bacteria into blood, lung and other tissues. Although topical and systemic antibiotics are routinely used, sepsis is the most common cause of prolonged hospitalization and death in burn patients that survive the initial insult. The frequency and severity of sepsis is exacerbated by the increasing prevalence of antibiotic resistant bacteria. Therefore, there is a need for new treatments to improve resistance to infection in severely burned patients. Our studies show that treatment with the toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) is effective in improving innate host resistance to Pseudomonas aeruginosa burn wound sepsis in mice. MPLA has low toxicity and is currently used widely as a vaccine adjuvant in the clinical setting. However, the mechanisms by which MPLA augments the host response to systemic bacterial infections are not well understood and further work is needed to translate the use of MPLA in high risk patients to the clinical setting. The goal of this project is to identify the cellular and molecular mechanisms by which TLR4-targeted immunomodulators, such as MPLA, improve innate host resistance to infection in high risk subjects. Pre-clinical studies will establish the safety and efficacy of MPLA in large animal models of burn wound infection and post-burn pneumonia. Specific Aim 1: To define the cellular mechanisms by which MPLA augments innate antimicrobial functions. This aim will test the hypothesis that treatment with MPLA will improve the response to infection after burn injury by inducing G-CSF-mediated expansion of the bone marrow neutrophil pool and causing augmentation of neutrophil chemotaxis. Specific aim 2: To define intracellular signaling alterations by which MPLA augments resistance to infection. This aim will test the hypothesis that MPLA treatment will cause alterations in infection-induced signaling resulting in predominance of the protective PI3K and Trif/IRF-3/IFN¿ pathways. Specific Aim 3: To determine the safety and efficacy of MPLA in an ovine model of burn wound infection and post-burn pneumonia. This aim will test the hypothesis that MPLA will be well tolerated in burned sheep and will improve their response to wound infection and pneumonia. The results gained in the proposed studies will facilitate the translation of TLR4-targeted immunomodulators into the clinical setting and will fill important gaps in knowledge by advancing our understanding of the cellular and molecular mechanisms by which TLR-based immunomodulators improve host resistance to infections.